In order to effectively manifest the efficacy of a pharmaceutical product, it is required to cause a pharmacologically active compound to act on an appropriate site in the body at an appropriate concentration for an appropriate length of time. Particularly, when systematically administered by intravenous administration or the like, a cytotoxic antitumor agent is widely distributed over the whole body and exhibits cell proliferation inhibitory action. In this case, it is reported that since cells are subjected to the pharmacological action without distinction between cancer cells and normal cells, serious side effects are brought about due to the action on the normal cells. Therefore, in order to reduce side effects, a technology of transporting the antitumor agent to a tumor lesion is important. Thus, there is a demand for a method for controlling the pharmacokinetics in order to selectively transport an antitumor agent to a tumor tissue and to cause the antitumor agent to act at an appropriate drug concentration for an appropriate time for manifesting the effect of the drug.
As a method for controlling the pharmacokinetics, a method of utilizing the pharmacokinetic characteristics based on the molecular weight is known. That is, when a biocompatible polymer material is intravascularly administered, renal excretion is suppressed, and a long half-life in blood is maintained. Furthermore, although recovery mechanism of polymer materials is not sufficiently constructed in the tumor tissue, it is known that tumor tissues have high tissue permeability of polymer materials, and that polymer materials are distributed and concentrated in tumor tissues at relatively high concentrations. Thus, polymerized antitumor agent derivatives in which a biocompatible polymer material is used as a polymer carrier and an antitumor agent is bonded to this polymer carrier, has been developed.
As such polymerized antitumor agents, polymer derivatives of antitumor agents have been reported, in which a block copolymer obtained by linking a polyethylene glycol segment and a polyglutamic acid segment is used as a polymer carrier, and various antitumor agents are bonded to side-chain carboxylic acids of the polyglutamic acid segment. Patent Document 1 discloses a pharmaceutical product in which 7-ethyl-10-hydroxycamptothecin is bonded to the relevant block copolymer. Furthermore, as other antitumor agents, a block copolymer conjugate of a cytidine-based antitumor agent (Patent Document 2), a block copolymer conjugate of combretastatin A-4 (Patent Document 3), a block copolymer conjugate of a HSP90 inhibitor (Patent Document 4), and the like are known. It is stated that these polymerized antitumor agents have enhanced antitumor effects, compared to those low molecular weight antitumor compounds used as active ingredients.
These block copolymer conjugates of antitumor agents are polymerized antitumor agents in which hydroxyl groups of the antitumor agent are bonded to side chain carboxylic acids of the block copolymer through ester bonds. These are prodrugs that exhibit antitumor activity when administered into the body, by cleaving the ester bonds at a constant rate to release the antitumor agent.
Furthermore, these block copolymers having antitumor agents bonded thereto have a physical property by which, when the block region to which the antitumor agent is bonded is hydrophobic, the antitumor agent-bonded region in an aqueous solution exhibits associative properties based on a hydrophobic interaction, and a plurality of the molecules of the block copolymer form associates through aggregation.
Associative aggregates formed by this polymerized antitumor agents may be detected by a light scattering analysis using laser light or the like, and the physical properties of the associative aggregates may be measured by means of the value of light scattering intensity. That is, the physical properties of the associative aggregates may be defined by taking the light scattering intensity as a measured value. For example, the block copolymer having an antitumor agent bonded thereto as described above has a physical property of forming nanoparticles that measure several nanometers to several hundred nanometers in size according to a particle size analysis based on a light scattering analysis method. Furthermore, similarly, in the measurement of the total molecular weight based on light scattering intensity measurement, it may be analyzed that the associative aggregates of the block copolymer having an antitumor agent bonded thereto are associates having a total molecular weight of several millions or more.
A polymerized antitumor agents having such associative properties behaves as nanoparticles in the body, thereby exhibiting pharmacokinetics such as described above, and is distributed at a high concentration in a tumor tissue. Then, the polymerized antitumor agent liberates an antitumor agent, thereby exhibiting a high antitumor effect. Therefore, for these polymerized antitumor agents, the associative properties of forming nanoparticles constitute an important factor for achieving the performance.
A drug-polymer conjugate pharmaceutical product such as described above is a pharmaceutical product that promotes high pharmacological activity and reduces side effects by means of the pharmacokinetics based on the molecular weight of the polymer carrier and by slowly releasing the drug bonded thereto as an active form. Therefore, such a drug-polymer conjugate pharmaceutical product needs to be prepared as a preparation which undergoes less change in the molecular weight of the polymer carrier under storage conditions, that is, a preparation having excellent storage stability with suppressed molecular weight reduction.
As a preparation provided with storage stability for a drug-polymer conjugate pharmaceutical product taken into consideration, for example, Patent Documents 5 and 6 disclose that changes in the molecular weight of the polymer carrier and liberation of the camptothecin derivative are suppressed by producing a conjugate of a polysaccharide having carboxyl groups and a camptothecin derivative into a pharmaceutical preparation including a sugar or a sugar alcohol and a pH adjusting agent.
However, in the drug-polymer conjugate pharmaceutical products described in Patent Documents 5 and 6, the drugs are bonded in a dispersed state to water-soluble polymer carriers, and therefore, it is speculated that the drug-polymer conjugate pharmaceutical products do not form associates in the form of nanoparticles. Thus, the molecular weight of the polymer carrier is considered to function as a performance-achieving factor. For this reason, molecular weight reduction by a chemical decomposition reaction caused by cleavage of chemical bonds of the carrier is a problem to be solved, and this suppression is the purpose of the invention. However, in regard to polymerized antitumor agents based on block copolymers, which employ polymerization by producing nanoparticles from associative aggregates as a performance-controlling factor, a stable pharmaceutical preparation intended to control the nanoparticle-forming ability has not been known.